Organic Chemistry Laboratory, University Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany.
University Clinic for Internal Medicine IV, Hematology/Oncology, Medical Faculty, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany.
Molecules. 2023 Jul 2;28(13):5173. doi: 10.3390/molecules28135173.
The purine derivative fludarabine is part of frontline therapy for chronic lymphocytic leukaemia (CLL). It has shown positive effects on solid tumours such as melanoma, breast, and colon carcinoma in clinical phase I studies. As the treatment of CLL cells with combinations of fludarabine and metal complexes of antitumoural natural products, e.g., illudin M ferrocene, has led to synergistically enhanced apoptosis, in this research study different complexes of fludarabine itself. Four complexes bearing a -[Br(PPh)]Pt/Pd fragment attached to atom C-8 via formal η-sigma or η-carbene bonds were synthesised in two or three steps without protecting polar groups on the arabinose or adenine. The platinum complexes were more cytotoxic than their palladium analogues, with low single-digit micromolar IC values against cells of various solid tumour entities, including cisplatin-resistant ones and certain B-cell lymphoma and CLL, presumably due to the ten-fold higher cellular uptake of the platinum complexes. However, the palladium complexes interacted more readily with isolated Calf thymus DNA. Interestingly, the platinum complexes showed vastly greater selectivity for cancer over non-malignant cells when compared with fludarabine.
嘌呤衍生物氟达拉滨是慢性淋巴细胞白血病（CLL）一线治疗的一部分。在 I 期临床试验中，它已显示出对黑色素瘤、乳腺癌和结肠癌等实体瘤的积极作用。由于用氟达拉滨和抗肿瘤天然产物的金属配合物（如艾鲁丁 M 二茂铁）联合治疗 CLL 细胞导致协同增强的细胞凋亡，因此在这项研究中，我们合成了不同的氟达拉滨自身配合物。通过正式的 η-σ 或 η-卡宾键，将 -[Br(PPh)]Pt/Pd 片段连接到通过原子 C-8 的阿拉伯糖或腺嘌呤上，合成了四个配合物。这些铂配合物比钯类似物具有更高的细胞毒性，对各种实体瘤细胞，包括顺铂耐药细胞和某些 B 细胞淋巴瘤和 CLL 的细胞，具有低个位数微摩尔的 IC 值，这可能是由于铂配合物的细胞摄取率高十倍。然而，钯配合物更容易与分离的小牛胸腺 DNA 相互作用。有趣的是，与氟达拉滨相比，铂配合物对癌细胞的选择性要高得多。
